Acute bacterial pneumonia is a significant source of morbidity and mortality worldwide. During pneumonia, the innate immune system rapidly detects and attacks pathogenic bacteria, while simultaneously initiating a parallel signaling system to limit collateral damage to local tissues. Our long-term goal is to develop therapeutic strategies that promote bacterial clearance while maintaining adequate tissue protection, and the first step is to better understand the signaling pathways involved. Our group has previously demonstrated that STAT3 is a key transcription factor at the center of these often-divergent outcomes, and its specific signaling depends largely on the milieu in which it is activated. The studies outlined in this proposal focus on two STAT3 activating cytokines, Leukemia Inhibitory Factor (LIF) and Oncostatin M (OSM), which appear to differentially affect these outcomes. We have previously shown that LIF is a critical cytokine involved in limiting acute lung injury during pneumonia and that LIF may be responsible for controlling a host of genes linked to cell death during bacterial pneumonia, particularly in lung epithelium. Moreover, our preliminary data suggest that LIF neutralization exacerbates pneumonia-induced epithelial apoptosis, implicating LIF-STAT3 signaling as an important countermeasure for preserving lung tissue in the setting of acute pulmonary inflammation. Significantly less is known about the role of OSM-STAT3 signaling during pneumonia. We have shown that OSM is strongly induced during pneumonia, but its physiological significance has never been explored. Our preliminary studies indicate that OSM is necessary for neutrophil recruitment and possibly neutrophil directed bacterial killing during pneumonia, suggesting that LIF and OSM, while closely related, have distinct and critical roles. Interestingly, our initial results also suggest that OSM selectively promotes expression of the neutrophil chemokine CXCL5, implicating a novel axis whereby OSM-induced CXCL5 elicits neutrophil-mediated host defense. Studies proposed in the following aims will employ complementary approaches to test our central hypothesis that the IL-6 family cytokines, LIF and OSM have crucial but distinct roles in lung protection during pneumonia: Aim 1) Test the hypothesis that LIF directly targets epithelial cells during pneumonia to limit apoptosis and acute lung injury; and Aim 2) Test the hypothesis that Oncostatin M is necessary for CXCL5- mediated neutrophil recruitment and host defense during pneumonia. Our proposal is designed to advance our understanding of STAT3 biology as it pertains to lung protection in pneumonia. Results will specifically shed light on physiological significance of LIF and OSM, which may extend to other biological principles controlling the severity of acute lung injury. Ultimately, itis our hope that a better understanding of these signaling pathways will have clinical implications in the management of bacterial pneumonia and ARDS.